3-Aminopyrrolidone derivatives

ABSTRACT

3-aminopyrrolidone compounds and pharmaceutically acceptable salts thereof that are active as sodium and/or calcium channel modulators and therefore useful in preventing, alleviating and curing a wide range of pathologies, including, but not limited to cardiovascular, inflammatory, ophthalmic, urologic, metabolic and gastrointestinal diseases.

This invention is related to 3-aminopyrrolidone derivatives andanalogues of the following general formula I

and pharmaceutically acceptable salts thereof, that are active as sodiumand/or calcium channel modulators and therefore useful in preventing,alleviating and curing a wide range of pathologies, including, but notlimited to, neurological, psychiatric, cardiovascular, inflammatory,ophthalmic, urologic, metabolic and gastrointestinal diseases, where theabove mechanisms have been described as playing a pathological role.

BACKGROUND OF THE INVENTION

Chemical Background

WO97/05111 discloses N-(4-substituted-benzyl)-2-aminolactam derivativesof general formula II

wherein:

m is zero, 1, 2 or 3; n is zero, 1, 2 or 3; X is O, S, CH₂ or NH; eachof R and R₁ independently is hydrogen, C₁-C₆ alkyl, halogen, hydroxy,C₁-C₄ alkoxy or trifluoromethyl; each of R₂, R₃ and R₄ independently ishydrogen, C₁-C₆ alkyl optionally substituted by a hydroxy group, orC₃-C₇ cycloalkyl.

The compounds of the invention are active on the central nervous system(CNS) and can be used in therapy, for example as antiepileptics, in thetreatment of Parkinson's disease and as neuroprotective agents, e.g.preventing or treating neuronal loss associated with stroke, ischemia,CNS trauma, hypoglycaemia or surgery and in treating or preventingneurodegenerative diseases such as Alzheimer's disease, amyotrophiclateral sclerosis, Down's syndrome or Huntington's disease; they canalso be used as antidepressants, hypnotics and antispastic agents.

In WO 96/40679, WO 95/33719 and U.S. Pat. No. 3,714,175 N-substitutedpyrrolidone derivatives are claimed to be active as anticoagulants(Factor Xa), herbicidals and muscle relaxants, respectively.

In EP 0362941, N—OH substituted pyrrolidone derivatives are claimed tobe active as anticonvulsants, muscle relaxants and inanti-neurodegenerative disorders.

Biological Background

It is well known that sodium channels play an important role in theneuronal network by transmitting electrical impulses rapidly throughoutcells and cell networks, thereby coordinating higher processes rangingfrom locomotion to cognition. These channels are large transmembraneproteins, which are able to switch between different states to enableselective permeability for sodium ions. For this process an actionpotential is needed to depolarize the membrane, and hence these channelsare voltage-gated. In the past few years a much better understanding ofsodium channels and drugs interacting with them has been developed.

It has become clear that a number of drugs having an unknown mechanismof action actually act by modulating sodium channel conductance,including local anesthetics, class I antiarrhythmics andanticonvulsants. Neuronal sodium channel blockers have found applicationwith their use in the treatment of epilepsy (phenyloin andcarbamazepine), bipolar disorder (lamotrigine), preventingneurodegeneration, and in reducing neuropathic pain. Variousanti-epileptic drugs that stabilize neuronal excitability are effectivein neuropathic pain (gabapentin).

In addition, an increase in sodium channel expression or activity hasalso been observed in several models of inflammatory pain, suggesting arole of sodium channels in inflammatory pain.

Calcium channels are membrane-spanning, multi-subunit proteins thatallow controlled entry of calcium ions into cells from the extracellularfluid. Commonly, calcium channels are voltage dependent and are referredto as voltage sensitive calcium channels (VSCC). VSCCs are foundthroughout the mammalian nervous system, where they regulate such variedactivities as cellular excitability, transmitter release, intracellularmetabolism, neurosecretory activity and gene expression. All “excitable”cells in animals, such as neurons of the central nervous system (CNS),peripheral nerve cells, and muscle cells, including those of skeletalmuscles, cardiac muscles and venous and arterial smooth muscles, havevoltage dependent calcium channels. Calcium channels have a central rolein regulating intracellular calcium ions levels that are important forcell viability and function. Intracellular calcium ion concentrationsare implicated in a number of vital processes in animals, such asneurotransmitter release, muscle contraction, pacemaker activity, andsecretion of hormones. It is believed that calcium channels are relevantin certain disease states. A number of compounds useful in treatingvarious cardiovascular diseases in mammals, including humans, arethought to exert their beneficial effects by modulating functions ofvoltage dependant calcium channels present in cardiac and/or vascularsmooth muscle. Compounds with activity against calcium channels havealso been implicated for the treatment of pain. In particular N-typecalcium channels (Cav2.2), responsible for the regulation ofneurotransmitters, are thought to play a significant role in nociceptivetransmission, both due to their tissue distribution as well as from theresults of several pharmacological studies. This hypothesis has beenvalidated in the clinic by Zinocotide, a peptide derived from the venomof the marine snail, Conus Magus. A limitation in the therapeutic use ofthis peptide is that it has to be administered intrathecally in humans(Bowersox S. S. and Luther R. Toxicon, 1998, 36, 11, 1651-1658).

All together these findings indicate that compounds with sodium and/orcalcium channel blockade have a high therapeutic potential inpreventing, alleviating and curing a wide range of pathologies,including neurological, psychiatric, cardiovascular, urologic, metabolicand gastrointestinal diseases, where the above mechanisms have beendescribed as playing a pathological role.

There are many papers and patents which describe sodium channel and/orcalcium channel modulators or antagonists for the treatment ormodulation of a plethora of disorders, such as their use as localanesthetics, antiarrhythmics, antiemetics, antimanic depressants, agentsfor the treatment of unipolar depression, cardiovascular diseases,urinary incontinence, diarrhea, inflammation, epilepsy,neurodegenerative conditions, nerve cell death, anticonvulsants,neuropathic pain, migraine, acute hyperalgesia and inflammation, renaldisease, allergy, asthma, bronchospasm, dysmenorrhea, esophageal spasm,glaucoma, urinary tract disorders, gastrointestinal motility disorders,premature labour, obesity. A largely incomplete list is shown below.

An extensive and thorough prior art overview is reported in WO 03/057219(and references therein); a further selection of prior art is reportedin the following references: Alzheimer, C. Adv. Exp. Med. Biol. 2002,513, 161-181; Vanegas, H.; Schaible, H. Pain 2000, 85, 9-18; U.S. Pat.No. 5,051,403; U.S. Pat. No. 5,587,454; U.S. Pat. No. 5,863,952; U.S.Pat. No. 6,011,035; U.S. Pat. No. 6,117,841; U.S. Pat. No. 6,362,174;U.S. Pat. No. 6,380,198; U.S. Pat. No. 6,420,383; U.S. Pat. No.6,458,781; U.S. Pat. No. 6,472,530; U.S. Pat. No. 6,518,288; U.S. Pat.No. 6,521,647; WO 97/10210; WO 03/018561.

DESCRIPTION OF THE INVENTION

The present invention relates to the use of compounds of formula I

wherein

-   -   m is an integer from 1 to 3    -   X is methylene, oxygen, sulphur or a NR⁶ group;    -   R¹ is a straight or branched C₁-C₈ alkyl or C₃-C₈ alkenylene or        C₃-C₈ alkynylene chain, optionally substituted with CF₃, phenyl,        phenoxy or naphthyl, or phenyl, the aromatic rings optionally        substituted by one or more C₁-C₄ alkyl, halogens,        trifluoromethyl, hydroxy or C₁-C₄ alkoxy groups;    -   R², R³ are independently hydrogen, a C₁-C₃ alkyl chain, halogen,        trifluoromethyl, hydroxy or C₁-C₄ alkoxy groups;    -   R⁴, R⁵, R⁶ are independently hydrogen or C₁-C₆ alkyl;

and the pharmaceutically acceptable salts thereof for the preparation ofa medicament for the treatment of pain, migraine, cognitive disorders,inflammation, gastrointestinal tract disorders, disorders of thegenito-urinary tract, ophthalmic diseases, obesity.

This invention is also related to the compounds of the general formula Iwherein m, X, R¹, R², R³, R⁴, R⁵ and R⁶ are as defined above with theproviso that:

-   -   when R¹ is phenyl, benzyl, 2-phenethyl or 3-phenpropyl        optionally and independently substituted on the phenyl ring by        one or two C₁-C₆ alkyl, halogen, hydroxy, C₁-C₄ alkoxy or        trifluoromethyl; X is oxygen, sulphur, methylene or —NH—, at        least one of R² and R³ is other than hydrogen;

The disclaimed compounds are known from WO97/05111.

-   -   if m is 3, R¹—X 4-benzyloxy, R², R⁴ and R⁵ hydrogen then R³ is        other than 3-methoxy (CGX-0154772), and    -   if m is 3, R¹—X 3-benzyloxy, R², R⁴ and R⁵ hydrogen then R³ is        other than 4-methoxy (CGX-0154682).

The optional substituents R¹—X, R² and R³ in the phenyl ring may be inany position.

The pharmaceutically acceptable salts of the compounds of formula Iinclude acid addition salts with inorganic, e.g. hydrochloric,hydrobromic, sulphuric, and phosphoric acids or organic, e.g. acetic,propionic, benzoic, cinnamic, mandelic, salicylic, glycolic, lactic,oxalic, malic, maleic, malonic, fumaric, tartaric, citric, and the like.

Preferred use compounds of the invention are the compounds of formula Iwherein m is 1 or 2, X is oxygen or methylene or NH or NCH₃, R¹ is C₁-C₈alkyl chain, optionally substituted with CF₃, phenyl or phenoxy group,where the aromatic ring in R¹ is optionally substituted by one or twohalogen or methoxy or trifluoromethyl groups, R² and R³ are hydrogen,methyl, methoxy, fluorine, chlorine or bromine, R⁴ and R⁵ are hydrogenor methyl, halogen is chlorine or fluorine.

Examples of specific use compounds of the invention are:

-   3-(4-Butyloxy-benzylamino)-pyrrolidin-2-one;-   3-[4-(4-trifluorobutyloxy)-benzylamino]-pyrrolidin-2-one;-   3-(4-Pentyloxy-benzylamino)-pyrrolidin-2-one;-   3-[4-(5-trifluoropentyloxy)-benzylamino)-pyrrolidin-2-one;-   3-(4-Phenylethyl-benzylamino)-pyrrolidin-2-one;-   3-(4-Benzyloxy-benzylamino)-pyrrolidin-2-one;-   3-(4-Phenylbutoxy-benzylamino)-pyrrolidin-2-one;-   3-(4-Phenylpentoxy-benzylamino)-pyrrolidin-2-one;-   3-(4-Phenylallyloxy)-benzylamino-pyrrolidin-2-one;-   3-(4-Phenoxyethoxy-benzylamino)-pyrrolidin-2-one;-   3-[4-(Naphthalen-1-ylmethoxy)-benzylamino]-pyrrolidin-2-one;-   3-(4-Pentyloxy-3-fluoro-benzylamino)-pyrrolidin-2-one;-   3-(4-Pentyloxy-3-chloro-benzylamino)-pyrrolidin-2-one;-   3-(4-Pentyloxy-3-bromo-benzylamino)-pyrrolidin-2-one;-   3-(4-Pentyloxy-3-methoxy-benzylamino)-pyrrolidin-2-one;-   3-(4-Pentyloxy-3-methyl-benzylamino)-pyrrolidin-2-one;-   3-(4-Benzyloxy-3-fluoro-benzylamino)-pyrrolidin-2-one;-   3-(4-Benzyloxy-3-bromo-benzylamino)-pyrrolidin-2-one;-   3-(4-Benzyloxy-3-methoxy-benzylamino)-pyrrolidin-2-one;-   3-(4-Benzyloxy-3-methyl-benzylamino)-pyrrolidin-2-one;-   3-(4-Phenylpentoxy-2-chloro-benzylamino)-pyrrolidin-2-one;-   3-(4-Phenylpentoxy-3-bromo-benzylamino)-pyrrolidin-2-one;-   3-(4-Phenylpentoxy-3-methoxy-benzylamino)-pyrrolidin-2-one;-   3-(4-Phenylpentoxy-3-methyl-benzylamino)-pyrrolidin-2-one;-   3-(4-Phenylallyloxy-2-chloro-benzylamino)-pyrrolidin-2-one;-   3-(4-Phenylallyloxy-3-fluoro-benzylamino)-pyrrolidin-2-one;-   3-(4-Phenylallyloxy-3-bromo-benzylamino)-pyrrolidin-2-one;-   3-(4-Phenylallyloxy-3-methoxy-benzylamino)-pyrrolidin-2-one;-   3-(4-Phenylallyloxy-3-methyl-benzylamino)-pyrrolidin-2-one;-   3-(4-Phenoxyethoxy-2-chloro-benzylamino)-pyrrolidin-2-one;-   3-(4-Phenoxyethoxy-3-fluoro-benzylamino)-pyrrolidin-2-one;-   3-(4-Phenoxyethoxy-3-bromo-benzylamino)-pyrrolidin-2-one;-   3-(4-Phenoxyethoxy-3-methoxy-benzylamino)-pyrrolidin-2-one;-   3-(4-Phenoxyethoxy-3-methyl-benzylamino)-pyrrolidin-2-one;-   3-[4-(Naphthalen-1-ylmethoxy)-3-bromo-benzylamino]-pyrrolidin-2-one;-   3-[4-(Naphthalen-1-ylmethoxy)-3-methoxy-benzylamino]-pyrrolidin-2-one;-   3-[4-(Naphthalen-1-ylmethoxy)-3-methyl-benzyl    amino]-pyrrolidin-2-one;-   3-(4-Pentyloxy-3-bromo-5-methoxy-benzylamino)-pyrrolidin-2-one;-   3-(4-Pentyloxy-3,5-dimethoxy-benzylamino)-pyrrolidin-2-one;-   3-(4-Pentyloxy-3,5-dimethyl-benzylamino)-pyrrolidin-2-one;-   3-(4-Benzyloxy-3-bromo-5-methoxy-benzylamino)-pyrrolidin-2-one;-   3-(4-Benzyloxy-3,5-dimethoxy-benzylamino)-pyrrolidin-2-one;-   3-(4-Benzyloxy-3,5-dimethyl-benzylamino)-pyrrolidin-2-one;-   3-(4-Phenylallyloxy-3-bromo-5-methoxy-benzylamino)-pyrrolidin-2-one;-   3-(4-Phenylallyloxy-3,5-dimethoxy-benzylamino)-pyrrolidin-2-one;-   3-(4-Phenylallyloxy-3,5-dimethyl-benzylamino)-pyrrolidin-2-one;-   3-(4-Phenylpentoxy-3-bromo-5-methoxy-benzylamino)-pyrrolidin-2-one;-   3-(4-Phenylpentoxy-3,5-dimethoxy-benzylamino)-pyrrolidin-2-one;-   3-(4-Phenylpentoxy-3,5-dimethyl-benzylamino)-pyrrolidin-2-one;-   3-(4-Phenoxyethoxy-3-bromo-5-methoxy-benzylamino)-pyrrolidin-2-one;-   3-(4-Phenoxyethoxy-3,5-dimethoxy-benzylamino)-pyrrolidin-2-one;-   3-(4-Phenoxyethoxy-3,5-dimethyl-benzylamino)-pyrrolidin-2-one;-   3-[4-(Naphthalen-1-ylmethoxy)-2-chloro-5-methoxy-benzylamino]-pyrrolidin-2-one;-   3-[4-(Naphthalen-1-ylmethoxy)-3-fluoro-5-methoxy-benzylamino]-pyrrolidin-2-one;-   3-[4-(Naphthalen-1-ylmethoxy)-3-bromo-5-methoxy-benzylamino]-pyrrolidin-2-one;-   3-[4-(Naphthalen-1-ylmethoxy)-3,5-dimethoxy-benzylamino]-pyrrolidin-2-one;-   3-[4-(Naphthalen-1-ylmethoxy)-3,5-dimethyl-benzylamino]-pyrrolidin-2-one;-   3-[4-(2-Fluorobenzyloxy)-benzylamino]-pyrrolidin-2-one;-   3-[4-(2-Fluorobenzyloxy)-benzylamino]-N-methylpyrrolidin-2-one;-   3-[4-(2-triFluoromethyl-benzyloxy)-benzylamino]-pyrrolidin-2-one;-   3-[4-(2-Chlorobenzyloxy)-benzylamino]-pyrrolidin-2-one;-   3-[4-(2-Methoxybenzyloxy)-benzylamino]-pyrrolidin-2-one;-   3-[4-(3-Fluorobenzyloxy)-benzylamino]-pyrrolidin-2-one;-   3-[4-(3-Fluorobenzyloxy)-benzylamino]-N-methylpyrrolidin-2-one;-   3-{N-[4-(3-Fluorobenzyloxy)-benzyl]-N-methyl}-amino-pyrrolidin-2-one;-   3-[4-(3-triFluoromethyl-benzyloxy)-benzylamino]-pyrrolidin-2-one;-   3-[4-(3-Chlorobenzyloxy)-benzylamino]-pyrrolidin-2-one;-   3-[4-(3-Methoxybenzyloxy)-benzylamino]-pyrrolidin-2-one;-   3-[4-(3-Methoxybenzyloxy)-benzylamino]-N-methylpyrrolidin-2-one;-   3-[4-(4-Fluorobenzyloxy)-benzylamino]-pyrrolidin-2-one;-   3-[4-(4-Chlorobenzyloxy)-benzylamino]-pyrrolidin-2-one;-   3-[4-(4-Methoxybenzyloxy)-benzylamino]-pyrrolidin-2-one;-   3-[4-(4-triFluoromethyl-benzyloxy)-benzylamino]-pyrrolidin-2-one;-   3-[4-(2,3-diChlorobenzyloxy)-benzylamino]-pyrrolidin-2-one;-   3-[4-(3,4-diChlorobenzyloxy)-benzylamino]-pyrrolidin-2-one;-   3-[4-(3,4-diMethoxybenzyloxy)-benzylamino]-pyrrolidin-2-one;-   3-[4-(3,5-diMethoxybenzyloxy)-benzylamino]-pyrrolidin-2-one;-   3-[4-(3,5-diMethoxybenzyloxy)-benzylamino]-N-methylpyrrolidin-2-one;-   3-[4-(3,5-diMethoxyphenyl)-pentoxy]-benzylamino-pyrrolidin-2-one;-   3-[4-(2-Fluorobenzyloxy)-3-methyl-benzylamino]-pyrrolidin-2-one;-   3-[4-(2-triFluoromethyl-benzyloxy)-3-methyl-benzylamino]-pyrrolidin-2-one;-   3-[4-(3-Fluorobenzyloxy)-3-methyl-benzylamino]-pyrrolidin-2-one;-   3-{[4-(3-Fluorobenzyloxy)-3-methyl-benzyl]-N-methylamino}-pyrrolidin-2-one;-   3-[4-(3-triFluoromethyl-benzyloxy)-3-methyl-benzylamino]-pyrrolidin-2-one;-   3-[4-(3-Chlorobenzyloxy)-3-methyl-benzylamino]-pyrrolidin-2-one;-   3-{[4-(3-Chlorobenzyloxy)-3-methyl-benzyl]-N-methylamino}-pyrrolidin-2-one;-   3-[4-(3-Bromobenzyloxy)-3-methyl-benzylamino]-pyrrolidin-2-one;-   3-{[4-(3-Bromobenzyloxy)-3-methyl-benzyl]-N-methylamino}-pyrrolidin-2-one;-   3-[4-(4-triFluoromethyl-benzyloxy)-2-chloro-benzylamino]-pyrrolidin-2-one;-   3-[4-(4-Fluorobenzyloxy)-3-methyl-benzylamino]-pyrrolidin-2-one;-   3-[4-(4-triFluoromethyl-benzyloxy)-3-fluoro-benzylamino]-pyrrolidin-2-one;-   3-[4-(4-triFluoromethyl-benzyloxy)-3-bromo-benzylamino]-pyrrolidin-2-one;-   3-[4-(4-triFluoromethyl-benzyloxy)-3-methoxy-benzylamino]-pyrrolidin-2-one;-   3-[4-(4-triFluoromethyl-benzyloxy)-3-methyl-benzylamino]-pyrrolidin-2-one;-   3-[4-(4-Chlorobenzyloxy)-3-methyl-benzylamino]-pyrrolidin-2-one;-   3-[4-(4-triFluoromethyl-benzyloxy)-3-bromo-5-methoxy-benzylamino]-pyrrolidin-2-one;-   3-[4-(4-triFluoromethyl-benzyloxy)-3,5-dimethoxy-benzylamino]-pyrrolidin-2-one;-   3-[4-(4-triFluoromethyl-benzyloxy)-3,5-dimethyl-benzylamino]-pyrrolidin-2-one;-   3-[4-(3,4-diChlorobenzyloxy)-2-chloro-benzylamino]-pyrrolidin-2-one;-   3-[4-(3,4-diChlorobenzyloxy)-3-fluoro-benzylamino]-pyrrolidin-2-one;-   3-[4-(3,4-diChlorobenzyloxy)-3-bromo-benzylamino]-pyrrolidin-2-one;-   3-[4-(3,4-diChlorobenzyloxy)-3-methoxy-benzylamino]-pyrrolidin-2-one;-   3-[4-(3,4-diChlorobenzyloxy)-3-methyl-benzylamino]-pyrrolidin-2-one;-   3-[4-(3,5-diMethoxybenzyloxy)-2-chloro-benzylamino]-pyrrolidin-2-one;-   3-[4-(3,5-diMethoxybenzyloxy)-3-fluoro-benzylamino]-pyrrolidin-2-one;-   3-[4-(3,5-diMethoxybenzyloxy)-3-bromo-benzylamino]-pyrrolidin-2-one;-   3-[4-(3,5-diMethoxybenzyloxy)-3-methoxy-benzylamino]-pyrrolidin-2-one;-   3-[4-(3,5-diMethoxybenzyloxy)-3-methyl-benzylamino]-pyrrolidin-2-one;-   3-[4-(3,4-diChlorobenzyloxy)-3,5-dimethoxy-benzylamino]-pyrrolidin-2-one;-   3-[4-(3,4-diChlorobenzyloxy)-3,5-dimethyl-benzylamino]-pyrrolidin-2-one;-   3-[4-(3,5-diChlorobenzyloxy)-3-bromo-5-methoxy-benzylamino]-pyrrolidin-2-one;-   3-[4-(3,5-diMethoxybenzyloxy)-3-bromo-5-methoxy-benzylamino]-pyrrolidin-2-one;-   3-[4-(3,5-diMethoxybenzyloxy)-3,5-dimethoxy-benzylamino]-pyrrolidin-2-one;-   3-[4-(3,5-diMethoxyphenyl)-allyloxy)-3,5-dimethoxy-benzylamino]-pyrrolidin-2-one.-   3-(4-Benzyloxy-benzylamino)-piperidin-2-one;-   3-(4-Benzyloxy-benzylamino)-azepan-2-one;-   3-[4-(2-Fluorobenzyloxy)-benzylamino]-piperidin-2-one;-   3-[4-(2-Fluorobenzyloxy)-benzylamino]-azepan-2-one;-   3-[4-(2-Chlorobenzyloxy)-benzylamino]-piperidin-2-one;-   3-[4-(2-Chlorobenzyloxy)-benzylamino]-azepan-2-one;-   3-[4-(3-Fluorobenzyloxy)-benzylamino]-piperidin-2-one;-   3-[4-(3-Fluorobenzyloxy)-benzylamino]-azepan-2-one;-   3-[4-(4-Fluorobenzyloxy)-benzylamino]-piperidin-2-one;-   3-[4-(4-Fluorobenzyloxy)-benzylamino]-azepan-2-one;-   3-[4-(2-Chlorobenzylamino)-benzylamino]-piperidin-2-one;-   3-[4-(2-Chlorobenzylamino)-benzylamino]-azepan-2-one;-   3-{4-[(2-Chlorobenzyl)methylamino]-benzylamino}-piperidin-2-one;-   3-{4-[(2-Chlorobenzyl)methylamino]-benzylamino}-azepan-2-one;-   3-(4-Phenoxybenzylamino)-pyrrolidin-2-one;

or pharmaceutically acceptable salts thereof.

The compounds of the invention and the salts thereof can be obtained bya process comprising:

a) reaction of compounds of formula II

wherein R¹, R², R³ and X are as defined above

with compounds of formula III, in the presence of a reducing agent

wherein m and R⁵ are as defined previously thus obtaining a compound offormula I; or

b) reaction of compounds of formula IV

wherein R¹, R², R³ and X are as defined above and Y is a halogen atom ora O-EWG group, where the EWG means an electron withdrawing group, likee.g. mesyl, tosyl or trifluoroacetyl groups, able to transform theoxygen which they are linked to, in a good leaving group

with compounds of formula III thus obtaining a compound of formula I; or

c) reacting of a compound of formula V

wherein R¹, R², R³, R⁵, X and m are as defined above, with compounds offormula VI or VIIR⁴—Y  VIR⁷—CHO  VII

wherein Y is as defined above; R⁴ is as above defined and R⁷ is hydrogenor C₁-C₅ alkyl; and, if desired, converting a compound of the inventioninto another compound of the invention and/or, if desired, converting acompound of the invention into a pharmaceutically acceptable saltand/or, if desired, converting a salt into a free compound and/or, ifdesired, separating a mixture of isomers of compounds of the inventioninto a single isomer.

Compounds II, III, IV, VI and VII are commercially available compoundsor are prepared from commercially available compounds using well-knownmethods.

The reactions of compounds of formula II with compounds of formula IIIand of compounds of formula V with compounds of formula VII to give thecompounds of formula I is a reductive amination reaction which can becarried out according to known methods. According to a preferredembodiment of the invention, it may be performed under nitrogenatmosphere, in a suitable organic solvent, such as an alcohol, e.g. alower alkanol, in particular methanol, or in acetonitrile, or intetrahydrofuran, at a temperature ranging from about 0° C. to about 70°C., in the presence of a reducing agent, the most appropriate beingsodium borohydride or sodium cyanoborohydride. Occasionally Titanium IVisopropylate and molecular sieves can be added to the reaction mixturefor facilitating the reaction.

In a compound of formula IV and VI the halogen is preferably bromine oriodine. The alkylation reactions of a compound of formula IV with acompound of formula III and of a compound of formula V with a compoundof formula VI can be carried out in a suitable organic solvent, such asan alcohol, e.g. methanol, ethanol or isopropanol, in particular inethanol, at a temperature ranging from about 0° C. to about 50° C.

When in the compounds of the present invention and in theintermediate-products thereof, groups are present, which need to beprotected before submitting them to the above illustrated reactions,they may be protected before being reacted and then deprotectedaccording to well-known methods.

Pharmacology

The compounds of the invention display affinities for the calcium and/orsodium channel binding sites as demonstrated using selectiveradioligands in in vitro binding studies.

The compounds according to the invention are blockers of the voltagedependent sodium channels and/or calcium channels. These compoundstherefore displace 3H-batrachotoxin (BTX) with a high affinity from thebinding site on the sodium channel, with IC₅₀ in the low μM or sub μMrange. Similarly the compounds displace 3H-nitrendipine from the bindingsite in the calcium channel, with IC₅₀ in the low μM or most usually inthe sub μM range as well as inhibiting calcium influx induced throughcalcium channels via cellular depolarisation.

Such substances exhibit “use-dependency” when the sodium channels areblocked i.e. maximum blockage of the sodium channels is only achievedafter repeated stimulation of the sodium channel. Consequently, thesubstances preferably bind to sodium channels which are multiplyactivated. As a result the substances are capable of activitypreferentially in those regions of the body which are pathologicallyover-stimulated, as illustrated by patch-clamp experiments (W. A.Catteral, Trends Pharmacol. Sci., 8, 57-65; 1987) which show that thecompounds according to the invention block the electrically stimulatedsodium channel in a “use-dependent” manner.

The compounds of the invention are voltage dependent blockers of thecalcium and/or sodium channels as demonstrated by fluorescence calciuminflux assay and electrophysiological studies.

The N-type calcium channel modulating activity of the 3-aminopyrrolidonederivatives of general formula I was measured through a fluorescencebased calcium influx assay.

The sodium channel modulating activity of the 3-aminopyrrolidonederivatives of general formula I was measured throughelectrophysiological assays using the two electrodes voltage clamp(TEVC) technique in isolated Xenopus oocytes expressing the Na channelNav1.3.

As a consequence of these mechanisms the compounds of the invention areactive in vivo when orally administered in the range of 0.1 to 100 mg/kgin animal models such as the formalin model of persistent pain and thecarragenan model of inflammation.

In view of the above described mechanisms of action, the compounds ofthe present invention are useful in the treatment or prevention ofneuropathic pain. Neuropathic pain syndromes include, and are notlimited to: diabetic neuropathy; sciatica; non-specific lower back pain;multiple sclerosis pain; fibromyalgia; HIV-related neuropathy;neuralgia, such as post-herpetic neuralgia and trigeminal neuralgia; andpain resulting from physical trauma, amputation, cancer, toxins orchronic inflammatory conditions.

Compounds of the invention are also useful for the treatment of chronicpain. Chronic pain includes, and is not limited to, chronic pain causedby inflammation or an inflammatory-related condition, ostheoarthritis,rheumatoid arthritis, acute injury or trauma, upper back pain or lowerback pain (resulting from systematic, regional or primary spine disease(such as radiculopathy), bone pain, pelvic pain, spinal cordinjury-associated pain, cardiac chest pain, non-cardiac chest pain,central post-stroke pain, myofascial pain, cancer pain, geriatric painor pain caused by headache, temporomandibular joint syndrome, gout,fibrosis or thoracic outlet syndromes. In particular rheumatoidarthritis and ostheoarthritis.

Compounds of the invention are also useful in the treatment of acutepain (caused by acute injury, illness, sports-medicine injuries, carpaltunnel syndrome, burns, musculoskeletal sprains and strains,musculotendinous strain, cervicobrachial pain syndromes, dyspepsis,gastric ulcer, duodenal ulcer, dysmenorrhea, endometriosis or surgery(such as open heart or bypass surgery), post operative pain, kidneystone pain, gallbladder pain, gallstone pain, obstetric pain or dentalpain.

Compounds of the invention are also useful in the treatment of migraine,such as tension type headache, transformed migraine or evolutiveheadache, cluster headache, as well as secondary headache disorders,such as the ones derived from infections, metabolic disorders or othersystemic illnesses and other acute headaches, paroxysmal hemicrania andthe like, resulting from a worsening of the above mentioned primary andsecondary headaches.

Compounds of the invention are also useful for the treatment ofcognitive disorders.

Compounds of the invention are also useful for the treatment ofpsychiatric disorders. Psychiatric disorders include, and are notlimited to, bipolar disorder (such as bipolar disorder type I, bipolardisorder type II), cyclothymic disorder, rapid cycling, ultradiancycling, mania, hypomania, schizophrenia, schizophreniform disorders,schizoaffective disorders, delusional disorders, brief psychoticdisorders, shared psychotic disorders, psychotic disorder due to ageneral medical condition, substance-induced psychotic disorders or apsychotic disorder not otherwise specified, anxiety disorders andmoreover in smoke and drug addiction. In particular bipolar disorders,psychosis and addiction.

Compounds of the invention are also useful in the treatment ofperipheral diseases such as tinnitus.

Compounds of the invention inhibit inflammatory processes affecting allbody systems. Therefore are useful in the treatment of inflammatoryprocesses of the muscular-skeletal system of which the following is alist of examples but it is not comprehensive of all target disorders:arthritic conditions such as alkylosing spondylitis, cervical arthritis,fibromyalgia, gut, juvenile rheumatoid arthritis, lumbosacral arthritis,osteoarthritis, osteoporosis, psoriatic arthritis, rheumatic disease;disorders affecting skin and related tissues: eczema, psoriasis,dermatitis and inflammatory conditions such as sunburn; disorders of therespiratory system: asthma, allergic rhinitis and respiratory distresssyndrome, lung disorders in which inflammation is involved such asasthma and bronchitis; chronic obstructive pulmonary disease; disordersof the immune and endocrinological systems: periarthritis nodosa,thyroiditis, aplastic anaemia, sclerodoma, myasthenia gravis, multiplesclerosis, sarcoidosis, nephritic syndrome, Bechet's syndrome,polymyositis, gingivitis.

Compounds of the invention are also useful in the treatment ofgastrointestinal (GI) tract disorders such as inflammatory boweldisorders including but not limited to ulcerative colitis, Crohn'sdisease, ileitis, proctitis, celiac disease, enteropathies, microscopicor collagenous colitis, eosinophilic gastroenteritis, or pouchitisresulting after proctocolectomy and post ileonatal anastomosis, andirritable bowel syndrome including any disorders associated withabdominal pain and/or abdominal discomfort such as pylorospasm, nervousindigestion, spastic colon, spastic colitis, spastic bowel, intestinalneurosis, functional colitis, mucous colitis, laxative colitis andfunctional dyspepsia; but also for treatment of atrophic gastritis,gastritis varialoforme, ulcerative colitis, peptic ulceration, pyresis,and other damage to the GI tract, for example, by Helicobacter pylori,gastroesophageal reflux disease, gastroparesis, such as diabeticgastroparesis; and other functional bowel disorders, such asnon-ulcerative dyspepsia (NUD); emesis, diarrhea, and visceralinflammation.

Compounds of the invention are also useful in the treatment of disordersof the genito-urinary tract such as overactive bladder, prostatitis(chronic bacterial and chronic non-bacterial prostatitis), prostadynia,interstitial cystitis, urinary incontinence and benign prostatichyperplasia, annexities, pelvic inflammation, bartolinities andvaginitis. In particular overactive bladder and urinary incontinence.

Compounds of the invention are also useful in the treatment ofophthalmic diseases such as retinitis, retinopathies, uveitis and acuteinjury to the eye tissue, macular degeneration or glaucoma,conjunctivitis.

Compounds of the invention are also useful in the treatment of obesity.

Compounds of the invention are also useful for the treatment of allother conditions mediated by the inhibition of voltage gated sodiumchannels and/or voltage gated calcium channels.

It will be appreciated that the compounds of the invention mayadvantageously be used in conjunction with one or more other therapeuticagents. Examples of suitable agents for adjunctive therapy include a5HT_(1B/1D) agonist, such as a triptan (e.g. sumatriptan ornaratriptan); an adenosine A1 agonist; an EP ligand; an NMDA modulator,such as a glycine antagonist; a substance P antagonist (e.g. an NK1antagonist); a cannabinoid; acetaminophen or phenacetin; a5-lipoxygenase inhibitor; a leukotriene receptor antagonist; a DMARD(e.g. methotrexate); gabapentin and related compounds; a tricyclicantidepressant (e.g. amitryptiline); a neurone stabilising antiepilepticdrug; a monoaminergic uptake inhibitor (e.g. venlafaxine); a matrixmetalloproteinase inhibitor; a nitric oxide synthase (NOS) inhibitor,such as an iNOS or an nNOS inhibitor; an inhibitor of the release, oraction, of tumor necrosis factor alpha; an antibody therapy, such asmonoclonal antibody therapy; an antiviral agent, such as a nucleosideinhibitor (e.g. (lamivudine) or an immune system modulator (e.g.interferon); an analgesic, such as a cyclooxygenase-2 inhibitor; a localanaesthetic; a stimulant, including caffeine; an H2-antagonist (e.g.ranitidine); a proton pump inhibitor (e.g. omeprazole); an antacid (e.g.aluminium or magnesium hydroxide; an antiflatulent (e.g. semethicone); adecongestant (e.g. phenylephrine, phenylpropanolamine, pseudoephedrine,oxymetazoline, epinephrine, naphazoline, xylometazoline,propylhexedrine, or levo-desoxyephedrine, naphazoline, xylometazoline,propylhexedrine, or levo-desoxyephedrine); antitussive (e.g. codeine,hydrocodone, carmiphen, carbetapentane, or dextramethorphan); adiuretic; or a sedating or non-sedating antihistamine. It is to beunderstood that the present invention covers the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof in combinationwith one or more therapeutic agents.

The compounds of the present invention are useful in human andveterinary medicine. It is to be understood that reference to treatmentincludes both treatments of established symptoms and prophylactictreatment, unless explicitly stated otherwise.

The 3-aminopyrrolidone derivatives of formula I as above defined can beadministered as the “active ingredient” of a pharmaceutically acceptablecomposition which can be prepared by conventional procedures, forinstance by mixing the active ingredient with pharmaceuticallyacceptable, therapeutically inert organic and/or inorganic carriermaterials.

The composition comprising the above defined 3-aminopyrrolidonederivatives can be administered in a variety forms, e.g. orally, in theform of tablets, troches, capsules, sugar or film coated tablets, liquidsolutions, emulsions or suspensions; rectally, in the form ofsuppositories; parenterally, e.g. by intramuscular or intravenousinjection or infusion; and transdermally.

Suitable pharmaceutically acceptable, therapeutically inert organicand/or inorganic carrier materials useful in the preparation of suchcomposition include, for example, water, gelatin, gum arabic, lactose,starch, cellulose, magnesium stearate, talc, vegetable oils,polyalkyleneglycols and the like. The composition comprising the3-aminopyrrolidone derivatives of formula I as above defined can besterilized and may contain further well known components, such as, forexample, preservatives, stabilizers, wetting or emulsifying agents, e.g.paraffin oil, mannide monooleate, salts to adjust osmotic pressure,buffers and the like.

For example, the solid oral forms may contain, together with the activeingredient, diluents, e.g. lactose, dextrose, saccharose, cellulose,corn starch or potato starch; lubricants, e.g. silica, talc, stearicacid, magnesium or calcium stearate, and/or polyethylene glycols;binding agents, e.g. starches, arabic gums, gelatin, methylcellulose,carboxymethylcellulose or polyvinyl pyrrolidone; disgregating agents,e.g. a starch, alginic acid, alginates or sodium starch glycolate;effervescing mixtures; dyestuffs; sweeteners; wetting agents such aslecithin, polysorbates, laurylsulphates; and, in general, non-toxic andpharmacologically inactive substances used in pharmaceuticalformulations. Said pharmaceutical preparations may be manufactured inknown manner, for example, by means of mixing, granulating, tabletting,sugar-coating, or film-coating processes.

The oral formulations comprise sustained release formulations that canbe prepared in conventional manner, for instance by applying an entericcoating to tablets and granules.

The liquid dispersion for oral administration may be e.g. syrups,emulsions and suspensions.

The syrups may contain as carrier, for example, saccharose or saccharosewith glycerine and/or mannitol and/or sorbitol.

Suspensions and emulsions may contain as a carrier, for example, anatural gum, agar, sodium alginate, pectin, methylcellulose,carboxymethyl-cellulose, or polyvinyl alcohol. The suspensions orsolutions for intramuscular injections may contain, together with theactive compound, a pharmaceutically acceptable carrier, e.g. sterilewater, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and, ifdesired, a suitable amount of lidocaine hydrochloride. The solutions forintravenous injections or infusion may contain as carrier, for example,sterile water or preferably they may be in the form of sterile, aqueous,isotonic saline solutions.

The suppositories may contain, together with the active ingredient, apharmaceutically acceptable carrier, e.g. cocoa butter, polyethyleneglycol, a polyoxyethylene sorbitan fatty acid ester surfactants orlecithin.

Suitable treatment is given 1, 2 or 3 times daily, depending uponclearance rate. Accordingly, the desired dose may be presented in asingle dose or as divided doses administered at appropriate intervals,for example two to four or more sub-doses per day.

The pharmaceutical compositions comprising the 3-aminopyrrolidonederivatives of formula I as above defined will contain, per dosage unit,e.g., capsule, tablet, powder injection, teaspoonful, suppository andthe like from about 0.1 to about 500 mg of the active ingredient mostpreferably from 1 to 10 mg.

Optimal therapeutically effective doses to be administered may bereadily determined by those skilled in the art and will vary, basically,with the strength of the preparation, with the mode of administrationand with the advancement of the condition or disorder treated. Inaddition, factors associated with the particular subject being treated,including subject age, weight, diet and time of administration, willresult in the need to adjust the dose to an appropriate therapeuticallyeffective level.

The following examples further illustrate the invention.

EXAMPLE 1 (S)-3-[4-(3-Fluorobenzyloxy)-benzylamino]-pyrrolidin-2-one

To a 2M solution of (S)-3-aminopyrrolidin-2-one (1.47 g, 14.6 mmol),prepared as described in Example 5, in anhydrous methanol 2.0 g of 3 Åmolecular sieves and 0.77 g NaBH₃CN (12 mmol) were added; after 10minutes, 3.4 g (14.8 mmol) of 4-(3-fluorobenzyloxy)benzaldeyde in 40 mlof anhydrous methanol were added. The reaction was carried out for 3hours, then the mixture filtered, the solution was evaporated yielding aresidue which was directly flash-chromatographed on silica gel (eluant:CHCl₃:CH₃OH:NH₃ (30%) 97:3:0.3, v:v:v) to give a white solid (3.4 g;74%). The free base thus obtained was treated with a stoichiometricamount of methanesulfonic acid to give the title compound m.p.140.5-143.5° C.

MS (ESI Pos Spray 3.5 kV; Skimmer 20 V; Probe 250° C.): 315 [MH⁺]

EXAMPLE 2(S)-3-{N-[4-(3-Fluorobenzyloxy)-benzyl]-N-methyl}-amino-pyrrolidin-2-one

1.0 g (3.2 mmol) of(S)-3-[4-(3-fluorobenzyloxy)-benzylamino]-pyrrolidin-2-one was dissolvedin 50 ml acetonitrile under inert conditions. 1.6 ml (20 mmol) of 37%formaldehyde and 0.29 g (4.6 mol) of sodium cyanoborohydride were addedat room temperature. After 20 minutes glacial acetic acid was addeduntil reaching a neutral pH value. The mixture was stirred for 40minutes and then evaporated to dryness. After adding 40 ml of 2Mpotassium hydroxide the product was extracted with ethyl acetate, theorganic layer was washed first with a 0.5 M KOH solution, then withwater and brine. The organic layer was dried over Na₂SO₄, then filteredand evaporated to obtain a residue which was flash-chromatographed onsilica gel (eluant: CHCl₃:CH₃OH:NH₃ (30%), 200:3:0.2, v:v:v) to give0.73 g (70%) of a white solid m.p. 89-92° C.

MS (ESI Pos Spray 3.5 kV; Skimmer 20 V; Probe 250° C.): 329 [MH⁺]

EXAMPLE 3(S)-3-[3,5-diMethyl-4-(4-trifluoromethyl-benzyloxy)-benzylamino]-pyrrolidin-2-one

2M solution of (S)-3-aminopyrrolidin-2-one (650 mg, 6.5 mmol), preparedas described in Example 5, in dry THF was added to a 1M solution of3,5-dimethyl-4-(4-trifluoromethyl-benzyloxy)-benzaldehyde (2.2 g, 7.15mmol), prepared as described in Example 6, in dry THF. To this mixture,a 2M solution of Ti(O-iPr)₄ (2.77 g, 9.75 mmol) in dry THF was addeddropwise and the reaction mixture was stirred 12 hours at roomtemperature under nitrogen.

A 0.75M solution of sodium borohydride (690 mg, 18.2 mmol) in absoluteethanol was added and the resulting mixture was heated at 70° C. for 6hours. After cooling, water (8 ml) was added and the resulting whiteprecipitate was removed by filtration. The crude compound was purifiedusing SCX cartridge (Strong Cation eXchange resin). The pure product wasrecovered by eluting with 3% ammonia solution in methanol. The titlecompound was obtained (2.24 g) after evaporating the solvent undervacuum with a yield of 88%.

MS (ESI Pos Spray 3.5 kV; Skimmer 20 V; Probe 250° C.): 393 [MH⁺]

¹H-NMR (DMSO-d₆) δ: 7.7 (m, 5H), 7.0 (s, 2H), 4.9 (s, 2H), 3.68 (s, 2H),3.15 (m, 3H), 2.22 (m, 7H), 1.7 (m, 1H).

EXAMPLE 4(S)-3-[4-(3,4-Dichloro-benzyloxy)-3-methyl-benzylamino]-pyrrolidin-2-one

2M solution of (S)-3-amino-pyrrolidin-2-one (650 mg, 6.5 mmol), preparedas described in Example 5, in dry THF was added to a 1M solution of4-(3,4-dichloro-benzyloxy)-3-methyl-benzaldehyde (2.1 g, 7.15 mmol),prepared as described in Example 7, in dry THF. To this mixture, a 2Msolution of Ti(O-iPR₄) (2.77 g, 9.75 mmol) in dry THF was added dropwiseand the reaction mixture was stirred 12 hours at room temperature undernitrogen.

A 0.75M solution of sodium borohydride (690 mg, 18.2 mmol) in absoluteethanol was added and the resulting mixture was heated at 70° C. for 6hours. After cooling, water (8 ml) was added and the resulting whiteprecipitate was removed by filtration. The crude compound was purifiedusing SCX cartridge (Strong Cation eXchange resin). The pure product wasrecovered by eluting with 3% ammonia solution in methanol. The titlecompound was obtained (2.18 g) after evaporating the solvent undervacuum with a yield 89%.

MS (ESI Pos Spray 3.5 kV; Skimmer 20 V; Probe 250° C.): 378.9 [MH⁺]

¹H-NMR (DMSO-d₆) δ: 7.72-7.68 (m, 3H), 7.45 (dd, 1H), 7.1 (m, 2H), 6.9(dd, 1H), 5.15 (s, 2H), 3.65 (s, 2H), 3.15 (m, 3H), 2.20 (m, 4H), 1.68(m, 1H).

EXAMPLE 5 (S)-3-amino-pyrrolidin-2-one

5M solution of hexamethyldisilazane (108 ml, 523 mmol) in CH₃CN wasadded dropwise to a solution of (S)-2,4-diamino-butyric acid (10 g, 52.3mmol) in CH₃CN (150 ml) at room temperature. The resulting mixture wasrefluxed for 30 hours. The crude reaction was poured into cold MeOH (400ml), stirred at room temperature for 30 minutes and then evaporatedunder vacuum. The resulting solid was dissolved in CH₂Cl₂ (700 ml) andthe insoluble residue was removed by filtration under vacuum.

The title compound was obtained (3.13 g) after evaporating the solutionto dryness in a 60% yield.

EXAMPLE 6 3,5-Dimethyl-4-(4-trifluoromethyl-benzyloxy)-benzaldehyde

0.5M solution of 1-bromomethyl-4-trifluoromethyl-benzene (1.9 g, 8.0mmol) in DMF was added dropwise to a suspension of4-hydroxy-3,5-dimethyl-benzaldehyde (930 mg, 7.3 mmol), K₂CO₃ (1.51 g,11 mmol) and KI (120 mg, 0.73 mmol) in DMF (100 ml). The reactionmixture was stirred at 90° C. overnight. After cooling, the solidresidue was filtered off and the solvent was evaporated under vacuum.The residue was dissolved in ethyl acetate and the organic layer washedtwice with NaOH 1M, dried over Na₂SO₄ and evaporated to dryness. Theresidue was purified on silica gel, obtaining 2.24 g of the titlecompound in a quantitative yield.

EXAMPLE 7 4-(3,4-diChloro-benzyloxy)-3-methyl-benzaldehyde

0.5M solution of 4-chloromethyl-1,2-dichloro-benzene (1.55 g, 8.0 mmol)in DMF was added dropwise to a suspension of4-hydroxy-3-methyl-benzaldehyde (990 mg, 7.3 mmol), K₂CO₃ (1.51 g, 11mmol) and KI (120 mg, 0.73 mmol) in DMF (100 ml). The reaction mixturewas treated as described in Example 6. The residue was purified onsilica gel, obtaining 2.15 g of the title compound in a quantitativeyield.

EXAMPLE 8

In Vitro Binding of ³H-Batrachotoxin in Rat Brain Membranes

Membrane preparations (P2 fraction) Male Wistar rats (Harlan,Italy—175-200 g) were sacrificed under light anaesthesia and brains wererapidly removed and cortex was dissected out, homogenized in 10 vol. ofice-cold 0.25 M sucrose buffer (50 mM Tris.HCl, pH 7.4). The crudehomogenate was centrifuged at 3250 rpm for 10 min and the supernatantrecovered. The pellet was homogenized and centrifuged again and the twosupernatants were pooled and centrifuged at 14750 rpm for 10 min, +4° C.The resulting pellet was stored at −20° C. until use.

Binding assay. The pellet was resuspended in 50 mM Hepes buffer, pH 7.4containing 0.8 mM MgSO₄, 5.4 mM KCl, 5.5 mM glucose and 130 mM cholineusing Polytron PT10. The binding assay was carried out in 0.25 ml finalvolume containing 50 μl of membrane preparation (ca 200 μg of protein),50 μl of ³H-batrachotoxin ligand (10 nM), 50 μl of TTX (1 μM), 50 μl ofscorpion toxin (37.5 μg/ml) and 50 μl of test compound or buffer or 300μM of veratridine to determine non specific binding. The binding assaywas performed at 37° C. for 30 min and stopped by rapid filtration undervacuum through Whatman GF/B glass fiber filters. Filters (pre-soakedwith polyethylenimine 0.1%) were washed with 3×5 ml of ice-cold bufferand placed in picovials containing scintillation cocktail (Filter Count,Packard). Radioactivity bound was measured by liquid scintillationspectrometry at 45% efficiency.

Data analysis. The IC₅₀ was calculated from displacement curves bycomputer program LIGAND (McPherson, J. Pharmacol. Methods, 14, 213.1985). The displacement curves were obtained using at least 9concentrations, each in duplicate, covering a 100000 fold range.

EXAMPLE 9

In Vitro Binding of ³H-Nitrendipine in Rat Brain Membranes

Membrane preparations Male Wistar rats (Harlan, Italy—175-200 g) weresacrificed under light anaesthesia and brains were rapidly removed andcortex was dissected out, homogenized in 10 vol. of ice-cold 50 mMTris.HCl, pH 7.7 using Polytron PT10. The crude homogenate wascentrifuged at 50000×g for 10 min. The pellet was homogenized andcentrifuged twice in fresh buffer at 50000×g for 10 min, +4° C. Theresulting pellet was stored at −20° C. until use.

Binding assay. The pellet was resuspended in 50 mM Tris HCl, pH 7.7using Polytron PT10. The binding assay was carried out in 1 ml finalvolume containing 900 μL of membrane preparation (ca 700 μg of protein),50 μl of ³H-nitrendipine (0.15 nM), and 50 μl of test compound or bufferor 1 μM of nifedipine to determine non specific binding. The bindingassay was performed at 25° C. for 45 min and stopped by rapid filtrationunder vacuum through Whatman GF/B glass fiber filters. Filters werewashed with 3×5 ml of ice-cold buffer and placed in picovials containingscintillation cocktail (Filter Count, Packard). Radioactivity bound wasmeasured by liquid scintillation spectrometry at 45% efficiency.

Data analysis. The IC₅₀ was calculated from displacement curves bycomputer program LIGAND (McPherson, J. Pharmacol. Methods, 14, 213.1985). The displacement curves were obtained using at least 9concentrations, each in duplicate, covering a 100000 fold range.

EXAMPLE 10

Calcium Influx Assay

IMR32 human neuroblastoma cells constitutively possess both L and N typechannels. Under differentiating conditions, IMR32 preferentially expresson the membrane surface N-type calcium channels. The remaining L-typecalcium channels were blocked using the selective L type blocker,nifedipine. In these experimental conditions, only N type channels canbe detected.

IMR32 cells were differentiated using 1 mM dibutyrril-cAMP and 2.5 μMbromodeoxyuridine for 8 days (4 times) in 225 cm² flask, then detached,seeded at 200,000 cells/well on 96 polilysine-coated plates and furtherincubated for 18-24 h in the presence of differentiating buffer beforeuse.

The Ca²⁺ Kit Assay (Molecular Devices), based on a fluorescent calciumindicator 485-535 nm wavelength, was used.

Differentiated cells were incubated with dye loading for 30 min at 37°C. then, nifedipine alone (1 μM) or in the presence of co-conotoxin ortest compounds were added for further 15 min.

The fluorescence (485-535 nm) was measured before and after (30-40 sec)the automated injection of 100 mM KCl depolarizing solution using aVictor plate reader (Perkin Elmer).

The inhibition curves were calculated from 5 concentrations, each intriplicate, and the IC₅₀ determined using a linear regression analysis.

Preferred compounds of general formula 1 inhibit N-type calcium channelswith an IC₅₀ value less than 10 μM.

EXAMPLE 11

Electrophysiological Assay

Experiments for the determination of the tonic block are carried out onisolated Xenopus oocytes expressing the Na channel Nav1.3. Currents arerecorded using the two electrodes voltage clamp (TEVC) technique.

Oocytes Preparation:

The frog (Xenopus Laevis) is anesthesized in a solution with3-aminobenzoic acid ethyl ester (1 g/l) and, after 25 minutes, it isplaced on its back on an “iced-bed”. The skin and the others tissues arecut, the ovarian lobes are pulled out and kept in ND96ØCa²⁺ (NaCl 96 mM,KCl 2 mM, MgCl2 1 mM, Hepes 10 mM, pH 7.85 with NaOH).

After the removal of the oocytes, the muscle and the skin are suturedseparately.

Ovarian lobes are reduced into clusters of 10/20 oocytes, put in tubeswith collagenase solution (1 mg/ml) and kept in movement for about 1 hin an incubator.

At the end of this step, when the oocytes are well separated ones fromthe others, they are rinsed three times with ND96ØCa²⁺ and three timeswith NDE (ND96ØCa²⁺+CaCl 0.9 mM, MgCl2 0.9 mM, piruvate 2.5 mM,gentamicine 50 mg/l).

The oocytes obtained are at different stages of development. Only cellsat stages V or VI are selected for RNA injection subsequent experiments.

The day after the preparation, the oocytes are injected (DrummondNanoject) with 20 ng Nav1.3 cRNA and maintained in NDE.

Starting from 48 h after the mRNA injection whole cell currents arerecorded using a two-microelectrode voltage clamp automated workstation.

Typical Microelectrodes have a resistance of 0.5 to 1 Mohm and arefilled with KCl 3M.

Control bath solution contains (mM): NaCl 98, MgCl₂ 1, CaCl₂ 1.8, HEPES5 (pH 7.6).

Compounds are prepared in stock solutions (20 mM) and dissolved to thefinal concentrations in the external bath solution.

Currents Recording:

The current/voltage (I/V) relationship for the Nav1.3 currents expressedin oocytes was first studied in order to determine the membranepotential evoking the maximal activation. Nav1.3 showed the maxactivation at 0 mV, that we used as test potential (Vtest) for tonicblock studies.

The steady-state inactivation properties of the Nav1.3 currents werethan studied in order to determine the membrane potentials for theresting state (Vrest) at which channel availability is maximal (Imax),and the membrane potential for the half maximal inactivation (V ½)producing half of the max current availability (I ½) respectively. Thistwo voltage conditions were then used for the evaluation of the voltagedependence of the tonic block.

Finally a two-step protocol was used to determine the voltage dependenceof the block of Nav1.3: the oocytes were clamped at −80 mV, the currentswere activated by a 100 ms step pulse to 0 mV (Vtest) from a 3000 mspreconditioning potential at −80 mV (resting, Imax condition) and −40 mV(depolarized, I ½ condition), respectively.

Current amplitudes in the two conditions were recorded in the absenceand in the presence of different concentrations of compound (washout wasmade in between) in order to determine the concentration—inhibitioncurves and IC₅₀ values for the tonic block in the depolarized (half maxcurrent availability) conditions.

Preferred compounds of general formula I inhibit Nav1.3 sodium channelswith an IC₅₀ value lower than the reference sodium channel blockerralfinamide.

EXAMPLE 12

Mice Formalin Test

According to a modified protocol from Rosland et al., (1990) mice wereinjected subcutaneously (s.c.) with 20 μl of 2.7% solution of formalininto the plantar surface of left hindpaw and placed immediately intoclear PVC observation chambers (23×12×13 cm). Pain behaviour wasquantified by counting the cumulative licking time (s) of the injectedpaw. Measurements were taken during the early phase (0-5 min) and latephase (30-40 min) after formalin injection (Tjolsen et al. 1992).

The test compound was administered p.o. 15 min before formalin injectionin a volume of 10 ml/kg body weight to groups of 10 mice per dose.Control group was treated with vehicle.

EXAMPLE 13

Carragenan Model of Inflammation

Male Wistar rats of 175-200 grams were used.

The left hind paw was injected with 100 μl of carrageenan (2% w/v insaline). Compounds of the invention (30 mg/kg), indomethacin (5 mg/kg)or control vehicle (such as distilled water) were orally administered 1h before carrageenan injection. The paw volume was measured with aplethysmometer (Ugo Basile) immediately before (basal) and 1, 2, 3, 4and 5 h after the carrageenan injection.

1-6. (canceled)
 7. A compound of general formula I

Wherein m is an integer from 1 to 3 X is methylene, oxygen, sulphur or aNR⁶ group; R¹ is a straight or branched C₁-C₈ alkyl or C₃-C₈ alkenyleneor C₃-C₈ alkynylene chain, optionally substituted with CF₃, phenyl,phenoxy or naphthyl or phenyl, the aromatic rings optionally substitutedby one or more C₁-C₄ alkyl, halogens, trifluoromethyl, hydroxy or C₁-C₄alkoxy groups; R², R³ are independently hydrogen, a C₁-C₃ alkyl chain,halogen, trifluoromethyl, hydroxy or C₁-C₄ alkoxy groups; R⁴, R⁵, R⁶ areindependently hydrogen or C₁-C₆ alkyl; and the pharmaceuticallyacceptable salts thereof.
 8. The compound according to claim 7, providedthat: when R¹ is phenyl, benzyl, 2-phenethyl or 3-phenpropyl optionallyand independently substituted on the phenyl ring by one or two C₁-C₆alkyl, halogen, hydroxy, C₁-C₄ alkoxy or trifluoromethyl and X isoxygen, sulphur, methylene or —NH—, at least one of R² or R³ is otherthan hydrogen; if m is 3, R¹—X 4-benzyloxy, R², R⁴ and R⁵ hydrogen thenR³ is other than 3-methoxy, and if m is 3, R¹—X 3-benzyloxy, R², R⁴ andR⁵ hydrogen then R³ is other than 4-methoxy.
 9. The use of a compoundaccording to claim 7 having the general formula I as specified in claim1, wherein m is 1 or 2, X is oxygen or methylene or NH or NCH₃, R¹ isC₁-C₈ alkyl chain, optionally substituted with CF₃, phenyl or phenoxygroup, where the aromatic ring in R¹ is optionally substituted by one ortwo halogen or methoxy or trifluoromethyl groups, R² and R³ arehydrogen, methyl, methoxy, fluorine, chlorine or bromine, R⁴ and R⁵ arehydrogen or methyl, halogen is chlorine or fluorine.
 10. The compoundaccording to claim 7 wherein the compound is selected from the groupconsisting of: 3-(4-Butyloxy-benzylamino)-pyrrolidin-2-one;3-[4-(4-trifluorobutyloxy)-benzylamino]-pyrrolidin-2-one;3-(4-Pentyloxy-benzylamino)-pyrrolidin-2-one;3-[4-(5-trifluoropentyloxy)-benzylamino]-pyrrolidin-2-one;3-(4-Phenylethyl-benzylamino)-pyrrolidin-2-one;3-(4-Benzyloxy-benzylamino)-pyrrolidin-2-one;3-(4-Phenylbutoxy-benzylamino)-pyrrolidin-2-one;3-(4-Phenylpentoxy-benzylamino)-pyrrolidin-2-one;3-(4-Phenylallyloxy)-benzylamino-pyrrolidin-2-one;3-(4-Phenoxyethoxy-benzylamino)-pyrrolidin-2-one;3-[4-(Naphthalen-1-ylmethoxy)-benzylamino]-pyrrolidin-2-one;3-(4-Pentyloxy-3-fluoro-benzylamino)-pyrrolidin-2-one;3-(4-Pentyloxy-3-chloro-benzylamino)-pyrrolidin-2-one;3-(4-Pentyloxy-3-bromo-benzylamino)-pyrrolidin-2-one;3-(4-Pentyloxy-3-methoxy-benzylamino)-pyrrolidin-2-one;3-(4-Pentyloxy-3-methyl-benzylamino)-pyrrolidin-2-one;3-(4-Benzyloxy-3-fluoro-benzylamino)-pyrrolidin-2-one;3-(4-Benzyloxy-3-bromo-benzylamino)-pyrrolidin-2-one;3-(4-Benzyloxy-3-methoxy-benzylamino)-pyrrolidin-2-one;3-(4-Benzyloxy-3-methyl-benzylamino)-pyrrolidin-2-one;3-(4-Phenylpentoxy-2-chloro-benzylamino)-pyrrolidin-2-one;3-(4-Phenylpentoxy-3-bromo-benzylamino)-pyrrolidin-2-one;3-(4-Phenylpentoxy-3-methoxy-benzylamino)-pyrrolidin-2-one;3-(4-Phenylpentoxy-3-methyl-benzylamino)-pyrrolidin-2-one;3-(4-Phenylallyloxy-2-chloro-benzylamino)-pyrrolidin-2-one;3-(4-Phenylallyloxy-3-fluoro-benzylamino)-pyrrolidin-2-one;3-(4-Phenylallyloxy-3-bromo-benzylamino)-pyrrolidin-2-one;3-(4-Phenylallyloxy-3-methoxy-benzylamino)-pyrrolidin-2-one;3-(4-Phenylallyloxy-3-methyl-benzylamino)-pyrrolidin-2-one;3-(4-Phenoxyethoxy-2-chloro-benzylamino)-pyrrolidin-2-one;3-(4-Phenoxyethoxy-3-fluoro-benzylamino)-pyrrolidin-2-one;3-(4-Phenoxyethoxy-3-bromo-benzylamino)-pyrrolidin-2-one;3-(4-Phenoxyethoxy-3-methoxy-benzylamino)-pyrrolidin-2-one;3-(4-Phenoxyethoxy-3-methyl-benzylamino)-pyrrolidin-2-one;3-[4-(Naphthalen-1-ylmethoxy)-3-bromo-benzylamino]-pyrrolidin-2-one;3-[4-(Naphthalen-1-ylmethoxy)-3-methoxy-benzylamino]-pyrrolidin-2-one;3-[4-(Naphthalen-1-ylmethoxy)-3-methyl-benzylamino]-pyrrolidin-2-one;3-(4-Pentyloxy-3-bromo-5-methoxy-benzylamino)-pyrrolidin-2-one;3-(4-Pentyloxy-3,5-dimethoxy-benzylamino)-pyrrolidin-2-one;3-(4-Pentyloxy-3,5-dimethyl-benzylamino)-pyrrolidin-2-one;3-(4-Benzyloxy-3-bromo-5-methoxy-benzylamino)-pyrrolidin-2-one;3-(4-Benzyloxy-3,5-dimethoxy-benzylamino)-pyrrolidin-2-one;3-(4-Benzyloxy-3,5-dimethyl-benzylamino)-pyrrolidin-2-one;3-(4-Phenylallyloxy-3-bromo-5-methoxy-benzylamino)-pyrrolidin-2-one;3-(4-Phenylallyloxy-3,5-dimethoxy-benzylamino)-pyrrolidin-2-one;3-(4-Phenylallyloxy-3,5-dimethyl-benzylamino)-pyrrolidin-2-one;3-(4-Phenylpentoxy-3-bromo-5-methoxy-benzylamino)-pyrrolidin-2-one;3-(4-Phenylpentoxy-3,5-dimethoxy-benzylamino)-pyrrolidin-2-one;3-(4-Phenylpentoxy-3,5-dimethyl-benzylamino)-pyrrolidin-2-one:3-(4-Phenoxyethoxy-3-bromo-5-methoxy-benzylamino)-pyrrolidin-2-one;3-(4-Phenoxyethoxy-3,5-dimethoxy-benzylamino)-pyrrolidin-2-one;3-(4-Phenoxyethoxy-3,5-dimethyl-benzylamino)-pyrrolidin-2-one;3-[4-(Naphthalen-1-ylmethoxy)-2-chloro-5-methoxy-benzylamino]-pyrrolidin-2-one;3-[4-(Naphthalen-1-ylmethoxy)-3-fluoro-5-methoxy-benzylamino]-pyrrolidin-2-one;3-[4-(Naphthalen-1-ylmethoxy)-3-bromo-5-methoxy-benzylamino]-pyrrolidin-2-one;3-[4-(Naphthalen-1-ylmethoxy)-3,5-dimethoxy-benzylamino]-pyrrolidin-2-one;3-[4-(Naphthalen-1-ylmethoxy)-3,5-dimethyl-benzylamino]-pyrrolidin-2-one;3-L4-(2-Fluorobenzyloxy)-benzylamino]-pyrrolidin-2-one;3-[4-(2-Fluorobenzyloxy)-benzylamino]-N-methylpyrrolidin-2-one;3-[4-(2-triFluoromethyl-benzyloxy)-benzylamino]-pyrrolidin-2-one;3-[4-(2-Chlorobenzyloxy)-benzylamino]-pyrrolidin-2-one;3-[4-(2-Methoxybenzyloxy)-benzylamino]-pyrrolidin-2-one;3-[4-(3-Fluorobenzyloxy)-benzylamino]-pyrrolidin-2-one;3-[4-(3-Fluorobenzyloxy)-benzylamino]-N-methylpyrrolidin-2-one;3-{N-[4-(3-Fluorobenzyloxy)-benzyl]-N-methyl}-amino-pyrrolidin-2-one;3-[4-(3-triFluoromethyl-benzyloxy)-benzylamino]-pyrrolidin-2-one;3-[4-(3-Chlorobenzyloxy)-benzylamino]-pyrrolidin-2-one;3-[4-(3-Methoxybenzyloxy)-benzylamino]-pyrrolidin-2-one;3-[4-(3-Methoxybenzyloxy)-benzylamino]-N-methylpyrrolidin-2-one;3-[4-(4-Fluorobenzyloxy)-benzylamino]-pyrrolidin-2-one;3-[4-(4-Chlorobenzyloxy)-benzylamino]-pyrrolidin-2-one;3-[4-(4-Methoxybenzyloxy)-benzylamino]-pyrrolidin-2-one;3-[4-(4-triFluoromethyl-benzyloxy)-benzylamino]-pyrrolidin-2-one;3-[4-(2,3-diChlorobenzyloxy)-benzylamino]-pyrrolidin-2-one;3-[4-(3,4-diChlorobenzyloxy)-benzylamino]-pyrrolidin-2-one;3-[4-(3,4-diMethoxybenzyloxy)-benzylamino]-pyrrolidin-2-one;3-[4-(3,5-diMethoxybenzyloxy)-benzylamino]-pyrrolidin-2-one;3-[4-(3,5-diMethoxybenzyloxy)-benzylamino]-N-methylpyrrolidin-2-one;3-[4-(3,5-diMethoxyphenyl)-pentoxy]-benzylamino-pyrrolidin-2-one;3-[4-(2-Fluorobenzyloxy)-3-methyl-benzylamino]-pyrrolidin-2-one;3-[4-(2-triFluoromethyl-benzyloxy)-3-methyl-benzylamino]-pyrrolidin-2-one;3-[4-(3-Fluorobenzyloxy)-3-methyl-benzylamino]-pyrrolidin-2-one;3-[4-(3-Fluorobenzyloxy)-3-methyl-benzyl]-N-methylamino}-pyrrolidin-2-one;3-[4-(3-triFluoromethyl-benzyloxy)-3-methyl-benzylamino]-pyrrolidin-2-one;3-[4-(3-Chlorobenzyloxy)-3-methyl-benzylamino]-pyrrolidin-2-one;3-{[4-(3-Chlorobenzyloxy)-3-methyl-benzyl]-N-methylamino}-pyrrolidin-2-one;3-[4-(3-Bromobenzyloxy)-3-methyl-benzylamino]-pyrrolidin-2-one;3-f[4-(3-Bromobenzyloxy)-3-methyl-benzyl]-N-methylamino}-pyrrolidin-2-one;3-[4-(4-triFluoromethyl-benzyloxy)-2-chloro-benzylamino]-pyrrolidin-2-one;3-[4-(4-Fluorobenzyloxy)-3-methyl-benzylamino]-pyrrolidin-2-one;3-[4-(4-triFluoromethyl-benzyloxy)-3-fluoro-benzylamino]-pyrrolidin-2-one;3-[4-(4-triFluoromethyl-benzyloxy)-3-bromo-benzylamino]-pyrrolidin-2-one;3-[4-(4-triFluoromethyl-benzyloxy)-3-methoxy-benzylamino]-pyrrolidin-2-one;3-[4-(4-triFluoromethyl-benzyloxy)-3-methyl-benzylamino]-pyrrolidin-2-one;3-[4-(4-Chlorobenzyloxy)-3-methyl-benzylamino]-pyrrolidin-2-one;3-[4-(4-triFluoromethyl-benzyloxy)-3-bromo-5-methoxy-benzylamino]-pyrrolidin-2-one;3-[4-(4-triFluoromethyl-benzyloxy)-3,5-dimethoxy-benzylamino]-pyrrolidin-2-one;3-[4-(4-triFluoromethyl-benzyloxy)-3,5-dimethyl-benzylamino]-pyrrolidin-2-one;3-[4-(3,4-diChlorobenzyloxy)-2-chloro-benzylamino]-pyrrolidin-2-one;3-[4-(3,4-diChlorobenzyloxy)-3-fluoro-benzylamino]-pyrrolidin-2-one;3-[4-(3,4-diChlorobenzyloxy)-3-bromo-benzylamino]-pyrrolidin-2-one;3-[4-(3,4-diChlorobenzyloxy)-3-methoxy-benzylamino]-pyrrolidin-2-one;3-[4-(3,4-diChlorobenzyloxy)-3-methyl-benzylamino]-pyrrolidin-2-one;3-[4-(3,5-diMethoxybenzyloxy)-2-chloro-benzylamino]-pyrrolidin-2-one;3-[4-(3,5-diMethoxybenzyloxy)-3-fluoro-benzylamino]-pyrrolidin-2-one;3-[4-(3,5-diMethoxybenzyloxy)-3-bromo-benzylamino]-pyrrolidin-2-one;3-[4-(3,5-diMethoxybenzyloxy)-3-methoxy-benzylamino]-pyrrolidin-2-one;3-[4-(3,5-diMethoxybenzyloxy)-3-methyl-benzylamino]-pyrrolidin-2-one;3-[4-(3,4-diChlorobenzyloxy)-3,5-dimethoxy-benzylamino]-pyrrolidin-2-one;3-[4-(3,4-diChlorobenzyloxy)-3,5-dimethyl-benzylamino]-pyrrolidin-2-one;3-[4-(3,5-diChlorobenzyloxy)-3-bromo-5-methoxy-benzylamino]-pyrrolidin-2-one;3-[4-(3,5-diMethoxybenzyloxy)-3-bromo-5-methoxy-benzylamino]-pyrrolidin-2-one;3-[4-(3,5-diMethoxybenzyloxy)-3,5-dimethoxy-benzylamino]-pyrrolidin-2-one;3-[4-(3,5-diMethoxyphenyl)-allyloxy)-3,5-dimethoxy-benzylamino]-pyrrolidin-2-one;3-(4-Benzyloxy-benzylamino)-piperidin-2-one;3-(4-Benzyloxy-benzylamino)-azepan-2-one;3-[4-(2-Fluorobenzyloxy)-benzylamino]-piperidin-2-one;3-[4-(2-Fluorobenzyloxy)-benzylamino]-azepan-2-one;3-[4-(2-Chlorobenzyloxy)-benzylamino]-piperidin-2-one;3-[4-(2-Chlorobenzyloxy)-benzylamino]-azepan-2-one;3-[4-(3-Fluorobenzyloxy)-benzylamino]-piperidin-2-one;3-[4-(3-Fluorobenzyloxy)-benzylamino]-azepan-2-one;3-[4-(4-Fluorobenzyloxy)-benzylamino]-piperidin-2-one;3-[4-(4-Fluorobenzyloxy)-benzylamino]-azepan-2-one;3-[4-(2-Chlorobenzylamino)-benzylamino]-piperidin-2-one;3-[4-(2-Chlorobenzylamino)-benzylamino]-azepan-2-one;3-{4-[(2-Chlorobenzyl)methylamino]-benzylamino}-piperidin-2-one;3-{4-[(2-Chlorobenzyl)methylamino]-benzylamino}-azepan-2-one;3-(4-Phenoxybenzylamino)-pyrrolidin-2-one; or pharmaceuticallyacceptable salts thereof.
 11. A process for the preparation of acompound of formula I, according to claim 7, or a pharmaceuticallyacceptable salt thereof, the process comprising: a) reaction ofcompounds of formula II

Wherein R¹, R², R³ and X are as defined above with compounds of formulaIII, in the presence of a reducing agent

wherein m and R⁵ are as defined previously thus obtaining a compound offormula I; or b) reaction of compounds of formula IV

IV wherein R¹, R², R³ and X are as defined above and Y is a halogen atomor a O-EWG group, where the EWG means an electron withdrawing group,like e.g. mesyl, tosyl or trifluoroacetyl groups, able to transform theoxygen which they are linked to, in a good leaving group with compoundsof formula III thus obtaining a compound of formula I; or c) reacting ofa compound of formula V

Wherein R¹, R², R³, R⁵, X and m are as defined above, with compounds offormula VI or VIIR⁴—Y  VIR⁷—CHO  VII wherein Y is as defined above; R⁴ is as above defined and R⁷is hydrogen or C₁-C₅ alkyl; and, if desired, converting a compound ofthe invention into another compound of the invention and/or, if desired,converting a compound of the invention into a pharmaceuticallyacceptable salt and/or, if desired, converting a salt into a freecompound and/or, if desired, separating a mixture of isomers ofcompounds of the invention into a single isomer.
 12. A pharmaceuticalcomposition containing a compound according to claim 7, or apharmaceutically acceptable salt thereof, in admixture with a suitablecarrier and/or diluent and optionally to other therapeutic agents.
 13. Amethod for treating pain, migraine, cognitive disorders, inflammation,gastrointestinal tract disorders, disorders of the genitor urinarytract, ophthalmic diseases or obesity in a subject comprisingadministering to said subject an effective amount of a compoundaccording to claim
 7. 14. A method for treating pain, migraine,cognitive disorders, inflammation, gastrointestinal tract disorders,disorders of the genitor urinary tract, ophthalmic diseases or obesityin a subject comprising administering to said subject an effectiveamount of a compound according to claim
 8. 15. A method for treatingpain, migraine, cognitive disorders, inflammation, gastrointestinaltract disorders, disorders of the genitor urinary tract, ophthalmicdiseases or obesity in a subject comprising administering to saidsubject an effective amount of a compound according to claim
 9. 16. Amethod for treating pain, migraine, cognitive disorders, inflammation,gastrointestinal tract disorders, disorders of the genitor urinarytract, ophthalmic diseases or obesity in a subject comprisingadministering to said subject an effective amount of a compoundaccording to claim 10.